The concept that various body tissues contain two dopamine receptors has only recently received general acceptance. These receptors have been designated as the D-1 and D-2 receptors. Several D-2 dopamine receptor agonists are known, including lergotrile and pergolide, both ergolines, and LY141865 (U.S. Pat. No. 4,148,415) an ergoline partial structure. These D-2 agonists have been found useful in treating Parkinson's disease as well as conditions in which there is an excess of circulating prolactin such as galactorrhea. LY141865 (trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline) has also been found to reduce blood pressure in mammals without the occurrence of postural hypertension. This antihypertensive activity is stated to be present in only one of the stereoisomers of the trans-(dl) racemate, the trans-(-)isomer, also named as 4aR,8aaR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline-see the copending application of Richard A. Hahn, Ser. No. 438,833, filed 11-3-82 now U.S. Pat. No. 4,468,401, issued 9-11-84. The same stereoisomer, as well as its parent racemate, has been found to be useful in treating sexual dysfunction in mammals--see the copending application of Mark M. Foreman, Ser. No. 518,906, filed 8-1-83, now abandoned, continuation-in-part application Ser. No. 636,959, filed 8-2-84.
Only a few drugs that affect the dopamine D-1 receptors are known. The first selective D-1 antagonist to be found was SCH-23390, R-(+)-7-hydroxy-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1M-3-benzaze pine--see Hyttel-Euro. J. Pharm., 91, 153 (1983) and, Iorio et al, J.P.E.T., 226, 462 (1983); see also U.S. Pat. No. 3,393,192 wherein the compounds are alleged to be anti-depressants, anti-bacterials, analgesics, and hypotensives.
SKF-38393, 1,2,3,4-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine, is claimed to be a dopamine D-1 agonist. Hahn and Wardell, J. Cardio-vascular. Pharm., 2, 583 (1980) describe the compound's activity as a renal vasodilator--see also Pendleton et al, Euro. J. Pharm., 51, 16 (1978). SKF-82526, 6-chloro-7,8-dihydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-(1H)-3-benza zepine has similar but improved properties--see Hahn et al, J.P.E.T., 223, 305 (1982), and Weinstock et al, J. Med. Chem., 23, 973 (1980). The compound is said to be a peripheral D-1 agonist without significant effect on central dopamine receptors, and is potentially useful in reversing the increased renal vascular resistance seen in many hypertensive patients.
Dopamine D-1 receptors, when stimulated by a D-1 agonist, are characterized by an increased cyclic AMP efflux. This effect is inhibited by D-2 agonists. Stoof and Kebabian discuss these D-1 agonist effects in papers appearing in Nature, 294, 266 (1981) and Brian Res., 250, 263 (1982). An in vitro effect of D-1 agonists in the nuclei accumbens and caudatus tissue of schizophrenics is an increase in the activation of adenylate cyclase.
Nothing in the cited prior art would indicate that the trans (+) enantiomorph of a trans (-) selective D-2 agonist would have any independant activity, much less any D-1 agonist activity.